OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation.

BACKGROUND: Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and apoptosis. While GTPase-related dysfunction is well-studied, the role of other OPA1 domains in ADOA pathology remains unclear. METHODS: To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts. RESULTS: Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier apoptosis, and distinct molecular pathway changes compared to V465F. CONCLUSIONS: This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.